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Functional variants in TBX2 are associated with a syndromic cardiovascular and skeletal developmental disorder.

Publication ,  Journal Article
Liu, N; Schoch, K; Luo, X; Pena, LDM; Bhavana, VH; Kukolich, MK; Stringer, S; Powis, Z; Radtke, K; Mroske, C; Deak, KL; McDonald, MT; Bick, D ...
Published in: Hum Mol Genet
July 15, 2018

The 17 genes of the T-box family are transcriptional regulators that are involved in all stages of embryonic development, including craniofacial, brain, heart, skeleton and immune system. Malformation syndromes have been linked to many of the T-box genes. For example, haploinsufficiency of TBX1 is responsible for many structural malformations in DiGeorge syndrome caused by a chromosome 22q11.2 deletion. We report four individuals with an overlapping spectrum of craniofacial dysmorphisms, cardiac anomalies, skeletal malformations, immune deficiency, endocrine abnormalities and developmental impairments, reminiscent of DiGeorge syndrome, who are heterozygotes for TBX2 variants. The p.R20Q variant is shared by three affected family members in an autosomal dominant manner; the fourth unrelated individual has a de novo p.R305H mutation. Bioinformatics analyses indicate that these variants are rare and predict them to be damaging. In vitro transcriptional assays in cultured cells show that both variants result in reduced transcriptional repressor activity of TBX2. We also show that the variants result in reduced protein levels of TBX2. Heterologous over-expression studies in Drosophila demonstrate that both p.R20Q and p.R305H function as partial loss-of-function alleles. Hence, these and other data suggest that TBX2 is a novel candidate gene for a new multisystem malformation disorder.

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Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

July 15, 2018

Volume

27

Issue

14

Start / End Page

2454 / 2465

Location

England

Related Subject Headings

  • Zebrafish
  • Young Adult
  • T-Box Domain Proteins
  • Pregnancy
  • Pedigree
  • Mice
  • Humans
  • Heart Defects, Congenital
  • Haploinsufficiency
  • Genetics & Heredity
 

Citation

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Liu, N., Schoch, K., Luo, X., Pena, L. D. M., Bhavana, V. H., Kukolich, M. K., … Yamamoto, S. (2018). Functional variants in TBX2 are associated with a syndromic cardiovascular and skeletal developmental disorder. Hum Mol Genet, 27(14), 2454–2465. https://doi.org/10.1093/hmg/ddy146
Liu, Ning, Kelly Schoch, Xi Luo, Loren D. M. Pena, Venkata Hemanjani Bhavana, Mary K. Kukolich, Sarah Stringer, et al. “Functional variants in TBX2 are associated with a syndromic cardiovascular and skeletal developmental disorder.Hum Mol Genet 27, no. 14 (July 15, 2018): 2454–65. https://doi.org/10.1093/hmg/ddy146.
Liu N, Schoch K, Luo X, Pena LDM, Bhavana VH, Kukolich MK, et al. Functional variants in TBX2 are associated with a syndromic cardiovascular and skeletal developmental disorder. Hum Mol Genet. 2018 Jul 15;27(14):2454–65.
Liu, Ning, et al. “Functional variants in TBX2 are associated with a syndromic cardiovascular and skeletal developmental disorder.Hum Mol Genet, vol. 27, no. 14, July 2018, pp. 2454–65. Pubmed, doi:10.1093/hmg/ddy146.
Liu N, Schoch K, Luo X, Pena LDM, Bhavana VH, Kukolich MK, Stringer S, Powis Z, Radtke K, Mroske C, Deak KL, McDonald MT, McConkie-Rosell A, Markert ML, Kranz PG, Stong N, Need AC, Bick D, Amaral MD, Worthey EA, Levy S, Undiagnosed Diseases Network (UDN), Wangler MF, Bellen HJ, Shashi V, Yamamoto S. Functional variants in TBX2 are associated with a syndromic cardiovascular and skeletal developmental disorder. Hum Mol Genet. 2018 Jul 15;27(14):2454–2465.
Journal cover image

Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

July 15, 2018

Volume

27

Issue

14

Start / End Page

2454 / 2465

Location

England

Related Subject Headings

  • Zebrafish
  • Young Adult
  • T-Box Domain Proteins
  • Pregnancy
  • Pedigree
  • Mice
  • Humans
  • Heart Defects, Congenital
  • Haploinsufficiency
  • Genetics & Heredity